Meloxicam belongs to the group of non-steroidal antiinflammatory drugs. It exerts its pharmacological effect by the inhibition of the cyclooxygenase (COX) enzyme system, which has significant role in the development of inflammatory processes. The medicinal importance of meloxicam resides in the fact that meloxicam selectively inhibits the COX-2 enzyme. This phenomenon results in less adverse effects during the medication period. It was found that the probability of the development of kidney-related or gastrointestinal adverse effects is significantly lower during the treatment using meloxicam than in those cases, when different, non-selective COX-inhibitors were administered.
Processes for the preparation of meloxicam have been disclosed in European Patent No. 2482. According to the first process, an activated form of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid of the Formula (III),
such as its methyl-, ethyl- or isopropyl ester (wherein the meaning of the R group in the Formula (III) is methyl, ethyl or isopropyl, respectively) is reacted with 2-amino-5-methyl-thiazole of the Formula (IV)
at high temperature. During this reaction, by-products with similar chemical structure to meloxicam and some tar are also formed, therefore further purification of the raw product is required. Solvents most often used for the recrystallization of raw meloxicam are dichloroethane and dichloromethane. The above mentioned process has the disadvantage that toxic and costly solvents are used, which are harmful to the environment as well. During the subsequent drying, it must be assured that the residual solvent concentration in the finished active ingredient should not exceed a threshold concentration set by health authorities and pharmacopoeias. At the drying temperature, thermal decomposition of the active ingredient also takes place. Use of halogenated organic solvents requires extensive analytical testing, because the residual solvent concentration must be determined in costly analytical measurements.
In the second known process, the nitrogen atom of the 2H-1,2-benzothiazine ring is methylated using either the very expensive methyl jodide or the extremely toxic dimethyl sulfate. Due to its low yield and high production costs, this process is not used on an industrial scale.
It was found that when using the above mentioned processes, the by-product 4-hydroxy-2-methyl-N-alkyl-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide of the Formula (V),
wherein the alkyl group corresponds identical to the R group in the starting compound of the Formula (III), i.e. methyl, ethyl or isopropyl, is formed in an amount of 1-20% by weight. Compounds of the Formula (V) are crystalline compounds poorly soluble in organic solvents and having their melting point above 250° C. Impurities of the Formula (V) can be removed partly by filtering the hot solution of meloxicam crude product. However, a dissolved portion of the compounds of Formula (V) amounting to a few tenth percent crystallizes together with meloxicam upon cooling, therefore compounds of the Formula (V) appear in the final pharmaceutical active ingredient as impurity. It was observed that the compounds of the Formula (V) are produced in the largest quantity (10-20% by weight), if the compound of the Formula (III) is used as starting material wherein R is methyl. The smallest amount of the compound of Formula (V) is produced in the case when R is isopropyl in the starting compound of the Formula (III). According to the specifications of the pharmacopoeias, threshold concentration of the compounds of the Formula (V) is 0.1% by weight, which could be achieved only after recrystallizing the crude product several times from dichloromethane.
United States Patent Application No. 20030109701 discloses processes for the preparation of several meloxicam polymorph forms by dissolving meloxicam in sodium-hydroxide solution prepared in water or in the mixture of water and an organic solvent, subsequently acidifying the solution of meloxicam sodium salt, thus setting meloxicam free from its sodium salt. In this way, different crystalline modifications of meloxicam are obtained, depending upon the conditions used during dissolution and precipitation. Subsequently, the polymorph form obtained in the above described process is converted into the pharmaceutically acceptable polymorph I form.